This section provides background information related to the present disclosure which is not necessarily prior art.
Opioid receptors are G protein-coupled receptors (GPCRs) that are activated both by endogenous opioid peptides and by clinically important alkaloid analgesic drugs such as morphine. There are three principal types of opioid receptors: the δ-opioid receptor, the κ-opioid receptor, and the μ-opioid receptor. Opioids depress respiration, which is controlled principally through medullary respiratory centers with peripheral input from chemoreceptors and other sources. Opioids produce inhibition at the chemoreceptors via μ-opioid receptors and in the medulla via μ- and δ-opioid receptors. While there are a number of neurotransmitters mediating the control of respiration, glutamate and γ-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters, respectively. Oxycodone and other opioid painkillers, as well as heroin and methadone are all implicated in fatal overdose.
In the United States, mortality rates closely correlate with opioid sales. In 2014, there were 47,055 drug overdose deaths in the United States, representing a 6.5% increase from 2013 as reported by Rudd et al. (2016) Morbidity & Mortality Weekly Report 64(50):1378-82 (starting at page 10) “Increases in Drug and Opioid Overdose Deaths—United States, 2000-2014.” Over 28,000 of those were overdoses of heroin or prescription opioids, which represents nearly a four-fold increase since 1999. Drugs classed as prescription opioids include both typical analgesics, such as OxyContin® (oxycodone HCl controlled-release) and methadone (used in the treatment of dependence on other opioids such as heroin and also prescribed for pain), but the increase in the rate of drug overdose in recent years has been driven mainlyby overdoses of prescription analgesics.
Naloxone is an opioid receptor antagonist that is approved for use by injection for the reversal of opioid overdose and for adjunct use in the treatment of septic shock. It is currently being used mainly in emergency departments and in ambulances by trained medical professionals. There have been efforts to expand its use by providing the drug to some patients with take-home opioid prescriptions and those who inject illicit drugs, potentially facilitating earlier administration of the drug.
U.S. Pat. No. 4,464,378 to Hussain reports a method for eliciting an analgesic or narcotic antagonist response in a warm-blooded animal, which comprises administering intranasally (IN) to said animal to elicit a narcotic antagonist response, a narcotic antagonist effective amount of naloxone.
WO 82/03768 to Hussain reports a composition that contains 1 mg of naloxone hydrochloride per 0.1 ml of solution adapted for nasal administration used in the treatment of narcotic induced respiratory depression (overdose) at a dosage approximately the same as that employed for intravenous (IV), intramuscular (IM) or subcutaneous (SQ) administration.
WO 00/62757 to Davies reports pharmaceutical compositions for IN or oral (PO) administration which comprise an opioid antagonist, such as naloxone for application by spray in the reversal of opioid depression for treatment of patients suffering from opioid over-dosage, wherein the spray applicator is capable of delivering single or multiple doses and suitable dosage units are in the range of 0.2 to 5 mg.
The use of nasal naloxone is not without controversy. For instance, Dowling et al. (Ther Drug Monit, Vol 30, No 4, August 2008) reported that naloxone administered intranasally displays a relative bioavailability of 4% only and concluded that the IN absorption is rapid but does not maintain measurable concentrations for more than an hour.
U.S. Pat. No. 9,192,570 to Wyse reports naloxone formulations for intranasal administration. Wyse reports (column 27, lines 29-37) that benzalkonium chloride is not suitable in such formulations, because it facilitates unacceptable degradation of the naloxone. Wyse recommends (lines 41-43) benzyl alcohol and paraben preservatives in place of benzalkonium chloride.
Thus, there remains a need for durable, easy-to-use, needleless devices with storage-stable formulations, that can enable untrained individuals to quickly deliver a therapeutically effective dose of a rapid-acting opioid antagonist to an opioid overdose patient. The therapeutically effective dose should be sufficient to obviate the need for the untrained individual to administer an alternative medical intervention to the patient, and to stabilize the patient until professional medical care becomes available.